This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD), a leading cause of morbidity and mortality in older adults, is characterized by cognitive impairment and neuropathological features, including beta amyloid (A ) deposition, neurofibrillary tangles, and increased cerebral inflammation. Convergent evidence has revealed an association between AD and insulin resistance. A substantial number of patients with AD demonstrate elevated fasting plasma insulin and reduced insulin sensitivity. These findings are supported by epidemiological studies that demonstrate an association between non-insulin dependent type-2 diabetes (NIDDM), a condition often associated with insulin resistance, and increased risk for memory impairment and AD (Kuisisto et al., 1997;Ott et al., 1999). We hypothesized that when treated early, insulin resistance and associated brain responses in AD may be reversible with tolerable doses of insulin sensitizer agents and that this treatment may also arrest, and potentially reverse, the clinical and neuropathological progression of AD type cognitive impairment. D-pinitol, an approved food supplement has been shown to have insulin-sensitizing effects in human studies. Moreover, in preclinical studies it interferes with the accumulation of beta amyloid, an important step in the development of Alzheimer's pathology. Hypothesis: The working hypothesis driving this application is that the insulin sensitizer agent d-pinitol, structurally related to the phosphatidylinositol phosphates that participate in insulin-mediated stimulation of glucose transport may beneficially influence AD-type amyloid neuropathology through inhibition of ?-secretase activity in the brain resulting in reduced generation of amyloidogenic A?1-42 and A?1-40 peptides